Presynaptic structure-function relationships at the vertebrate neuromuscular junction

The impact of presynaptic transmitter release site organization on synaptic function has been a vibrant area of research for synaptic physiologists. Because there is a highly nonlinear relationship between presynaptic calcium influx and subsequent neurotransmitter release at synapses, the organization and density of calcium sources (voltage-gated calcium channels [VGCCs]) relative to calcium sensors located on synaptic vesicles is predicted to play a major role in shaping the dynamics of neurotransmitter release at a synapse. Here we investigate neurotransmitter release at the neuromuscular junction across model preparations in an effort to discern the relationship between VGCC organization and synaptic function. We demonstrate that neurotransmitter release varies considerably across, but not within, individual synapses at the frog and mouse neuromuscular junction (NMJ). Further, we use a computational modeling approach to provide evidence that alterations in the spatiotemporal calcium dynamics within an AZ at the time of release, caused by manipulations in the density and organization of VGCCs, can explain variability in release. In addition, we use our model to demonstrate that VGCC organization is an important determinant of short-term plasticity, and that the differences in AZ arrangement between species can recapitulate the physiological differences between them. We use these studies to provide support for the notion that structure imparts function and argue that a fuller understanding of neurotransmitter release and plasticity must rely on an understanding of the spatio-temporal calcium dynamics at the time of vesicle release